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• DRL curves and DRLs for weight groups were derived and compared. • RDRLs were derived for five conventional and two CT examinations. • It may be beneficial to use DRL curves in clinics with a low number of examinations. To derive Regional Diagnostic Reference Levels (RDRL) for paediatric conventional and CT examinations using weight-based DRL curves and compare the outcome with DRL derived using the weight groups. Data from 1722 examinations performed at 29 hospitals in four countries were included. DRL was derived for four conventional x-ray (chest, abdomen, pelvis, hips/joints) and two types of CT examinations (thorax, abdomen). DRL curves were derived using an exponential fit to the data using weight as an independent variable and the respective radiation dose indices (P KA , CTDI vol , DLP) as dependent variables. DRL was also derived for weight groups for comparison. The result was compared with national diagnostic reference level (NDRL) curves. The derived curves show similarities with the NDRL curves available and corresponded sufficiently well with DRL for weight groups using the same data set, if sufficient number of data was available. We conclude that weight-based DRL curves are a feasible approach and could be used together with DRL for weight groups. The main advantage of DRL curves is its application in the clinic. When the examination frequency is low, time to collect enough data to establish typical values for one or several weight groups may be unreasonably long. The curve provides the means to compare dose level faster and with fewer data points. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: We previously published research on 4- and 8-year follow-ups of patient-reported sexual function after conventional external beam radiotherapy (EBRT) for localized prostate cancer (LPC) compared with age-matched controls. The current study is a prolonged 15-year follow-up with the same cohorts. Material and methods: The cohort consisted of 29 men surviving from a group of 181 men treated between 1986 and 1989, and who were reported on previously. Of the originally reported 141 controls, 62 were eligible and 34 completed the questionnaires. Sexual function was assessed using two questionnaires, Prostate Cancer Symptom Scale (PCSS) and International Index of Erectile Function (IIEF-5). Results: Twenty-three patients (78%) and 13 controls (38%) were not sexually active. None of the patients and 14 controls had enough of an erection to perform intercourse. Seventeen patients (94%) and 14 controls (64%) had severe erectile dysfunction. Patients with clinical progression and who had received hormone treatment had decreased sexual desire. No significant differences were measured between patients without progression/hormone treatment and the controls. Conclusion: The sexual activity 15 years after EBRT for LPC was very low, as was the probability of achieving an erection. Patients with a progressive disease and treated with hormones reported worse sexual and erectile function. The LPC free men showed higher sexual activity, lower sexual bother, and better erectile function than the patients. [Copyright &y& Elsevier]

Summary: Advanced prostate cancer with skeletal metastases entails significant symptoms from both treatment and the disease itself. Although the diagnosis is a common one, knowledge of the symptom experience late in the disease trajectory is limited. The aim of the present study was to describe the experience of physical symptoms in men with hormone refractory prostate cancer and skeletal metastases. Twenty men answered a quality of life questionnaire before participating in semi-structured interviews. The interviews were analyzed using qualitative description. Findings show that the dominant symptoms were lack of energy and pain. Interestingly when talking about lacking energy the men described three different variants; lack of mental energy or initiative, lack of strength and stamina, and tiredness or sleepiness. Also, three different types of pain were described; pain from skeletal metastases, a diffuse moving pain, and pain not directly caused by the prostate cancer. Though a majority of the men scored being dissatisfied with their sex life; in the interviews, this was not described as a major distress. The findings also showed that the men experienced different symptoms despite the same diagnosis, skeletal metastases, stage, and androgen deprivation treatment, and that these symptoms are not necessarily experienced as problems or causing distress. [Copyright &y& Elsevier]

Abstract: The disease trajectory of living with incurable cancer is characterized by increasing bodily deterioration and problems. In this paper, we have focused on the change in temporal awareness as manifested in the narrations of two men with hormone refractory prostate cancer and skeletal metastases as they approach death. The two men participated in in-depth research interviews during the last part of their lives, sharing a similar disease trajectory with increasing bodily change and decreasing physical function. Both died a lingering, cancer-related death. The first and last research interviews were analyzed using a discourse analytic method. Findings show that the temporal awareness in the interviews changes as the illness progresses and death approaches. In the last interviews, the present is flooded with bodily problems; the past and the future are hardly present except for the future beyond the men''s own deaths. Pain, fatigue, nausea, and other symptoms figure largely in this change, and there is no time for much more than attending to bodily needs in a present that is dominated by problems. Here, the importance of alleviating bodily problems once again becomes paramount, and two questions are raised: Is the often reported withdrawal from life, when death is imminent, a physical necessity rather than a psychological one, and is it possible to free time from the time-consuming problems of the present by means of a more concentrated attempt to alleviate these problems? [Copyright &y& Elsevier]

Background: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial.Methods: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321.Findings: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0·0001], rush to toilet [p=0·0013], flatulence [p=0·0013], bowel cramp [p<0·0001], mucus [p=0·0014], blood in stool [p<0·0001], and limitation in daily activity [p=0·0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5·1% [95% CI -4·4 to 14·6]; p=0·38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5·7% [-3·8 to 15·2]; p=0·33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9·1% [-1·4 to 19·6]; p=0·15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5·0% [-5·0 to 15·0]; p=0·41).Interpretation: Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer.Funding: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council. [ABSTRACT FROM AUTHOR]

Purpose: To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultrahypofractionated (UHF) radiation therapy (RT) or conventionally fractionated (CF) RT for prostate cancer.Methods and Materials: This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the HYPO-RT-PC trial (median follow-up 5, years), where patients were randomized to CF (39 × 2.0 Gy, 8 weeks) or UHF (7 × 6.1 Gy, 2.5 weeks). No androgen deprivation therapy was allowed. Only patients with erectile function sufficient for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (EDs). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning computed tomography scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/β = 3 Gy). Univariable and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS.Results: No significant difference in EDs was found between CF and UHF. During the follow-up period, EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2-year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years.Conclusions: The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiation therapy was the strongest predictor for EDs, followed by dose to PB, and was most evident for younger patients. We propose D2 % <50 Gy3 and Dmean <20 Gy3 to the PB as the primary objectives to be applied in the treatment planning process. [ABSTRACT FROM AUTHOR]

Background: Curative radiation therapy (RT) constitutes a cornerstone in prostate cancer (PC) treatment. We present long-term follow-up estimates for second cancer (SC) risk and overall survival (OS) in patients randomized to hormone therapy (ET) alone or combined with 70 Gy prostatic RT in the Scandinavian Prostate Cancer Group-7 (SPCG-7) study. We explored the effect of salvage RT (≥60 Gy to the ET group) and reported causes of death.Methods and Materials: The SPCG-7 study (1996-2002) was a randomized controlled trial that included 875 men with locally advanced nonmetastatic PC. In this analysis, including data from the Norwegian and Swedish Cancer and Cause of Death registries for 651 Norwegian and 209 Swedish study patients, we estimated hazard ratios (HRs) for SC and death, and cumulative incidences of SC.Results: Median follow-up of the 860 (431 ET and 429) ET + RT patients was 12.2 years for SC risk analysis and 12.6 years for the OS analysis. Eighty-three of the Norwegian ET patients received salvage RT, and median time to salvage RT was 5.9 years. We found 125 and 168 SCs in the ET and ET + RT patients, respectively. With ET alone as reference, ET + RT patients had an HR of 1.19 (95% confidence interval [CI], 0.92-1.54) for all SCs and 2.54 (95% CI, 1.14-5.69) for urinary bladder cancer (UBC). The total number of UBC was 31 (23 in ET + RT; 8 in ET), and the vast majority (85%) were superficial. The HR for SC in salvage RT patients was 0.48 (95% CI, 0.24-0.94). Median OS was 12.8 (95% CI, 11.8-13.8) and 15.3 (95%, CI 14.3-16.4) years in the ET and ET + RT groups, respectively. Compared with ET alone, the risk of death was reduced in ET + RT patients (HR, 0.73; 95% CI, 0.62-0.86) and in ET patients receiving salvage RT (HR, 0.44; 95% CI, 0.30-0.65).Conclusions: Although the risk of UBC was increased in PC patients who received RT in addition to ET, this disadvantage is outweighed by the OS benefit of RT confirmed in our study. The risk of SC, and especially UBC, should be discussed with patients and be reflected in follow-up programs. [ABSTRACT FROM AUTHOR]

Background: There is increasing low-quality evidence rationalizing the use of radical therapy for men at high risk of disseminated prostate cancer. Objective: To investigate, using high-quality epidemiologic data, whether initial radical therapy in men at high risk of disseminated prostate cancer improves survival. Design, setting, and participants: An observational population-based Swedish study from 1996 to 2010 of men at high risk of disseminated prostate cancer (prostate-specific antigen [PSA] > 50) initially treated by radical therapy (radiation therapy [n = 630] or radical prostatectomy [n = 120]) or androgen deprivation therapy (n = 17 602), and followed for up to 15 yr. Outcome measurements and statistical analysis: Prostate-cancer and other-cause mortality was estimated for the treatment groups. We also matched the two cohorts for grade, T stage, M stage, Charlson score, year of diagnosis, age, and PSA, and found androgen deprivation therapy patient matches for 575 of the radical therapy patients, and then repeated comparative effectiveness analyses. Results and limitation: Prostate-cancer mortality was substantially greater in the androgen deprivation therapy group compared with the radically treated one, in unmatched (9062/17 602 vs 86/750) and matched (177/575 vs 71/575) cohorts. Among matched cohorts, initial androgen deprivation therapy was associated with nearly three-fold higher hazard of prostate-cancer death compared with initial radical therapy (2.87; 95% confidence interval 2.16-3.82). Multiple sensitivity analyses suggested that the findings were robust, although the general limitations of nonrandomized studies remain. Further, the study cohort may have included men with both systemic and nonsystemic disease, as a sole eligibility criterion of PSA > 50 was used. Conclusions: This large and comprehensive population-based study suggests that initial radical therapy in men at high risk of disseminated prostate cancer improves survival. Patient summary: This large Swedish study suggests that men with prostate cancer that has spread beyond the prostate benefit from treating the prostate itself with radiation therapy or surgery rather than treating the disease with hormones alone. [ABSTRACT FROM AUTHOR]

Background Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives To identify molecular subgroups of PC bone metastases of relevance for therapy. Design, setting, and participants Fresh-frozen bone metastasis samples from men with CRPC ( n = 40), treatment-naïve PC ( n = 8), or other malignancies ( n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases ( n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease ( n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients ( n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation. Results and limitations The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes ( KLK2 , KLK3 , NKX3.1 , STEAP2 , TMPRSS2 ); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3 + and CD68 + cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression ( HLA-A , TAP1 , and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient. Conclusions Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the risk of thromboembolic disease (TED) after radiation therapy (RT) with curative intent for prostate cancer (PCa).Patients and Methods: We identified all men who received RT as curative treatment (n=9410) and grouped according to external beam RT (EBRT) or brachytherapy (BT). By comparing with an age- and county-matched comparison cohort of PCa-free men (n=46,826), we investigated risk of TED after RT using Cox proportional hazard regression models. The model was adjusted for tumor characteristics, demographics, comorbidities, PCa treatments, and known risk factors of TED, such as recent surgery and disease progression.Results: Between 2006 and 2013, 6232 men with PCa received EBRT, and 3178 underwent BT. A statistically significant association was found between EBRT and BT and risk of pulmonary embolism in the crude analysis. However, upon adjusting for known TED risk factors these associations disappeared. No significant associations were found between BT or EBRT and deep venous thrombosis.Conclusion: Curative RT for prostate cancer using contemporary methodologies was not associated with an increased risk of TED. [ABSTRACT FROM AUTHOR]

Background In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone. Objective To compare mortality rates in patients receiving ET alone versus ET + RAD. Design, settings, and participants From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70 Gy) at 3 mo. Outcome, measurements and statistical analysis PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models. Intervention RAD added to ET. Results and limitations With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29–39%) and 17% (95% confidence interval, 13–22%) in the ET and ET + RAD arms respectively ( p < 0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age ≥65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity. Conclusions In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa. Patient summary Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate long-term changes in the rectal mucosa after curative external beam radiation therapy in the treatment of prostate cancer.Methods and Materials: In the Scandinavian Prostate Cancer Group 7 trial, 880 men with locally advanced prostate cancer were randomized to hormonal therapy alone versus hormonal therapy plus radiation therapy to 70 Gy. A subcohort from this trial being randomized at our center (n=178) was invited to a study on late anorectal side effects during 2003-2005, approximately 5 years after treatment, including measuring health-reported quality of life and physician-assessed toxicity score by the Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic (LENT/SOMA) and European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group score. Sixty-seven patients had a rectal mucosa biopsy. Sixty-four biopsies were included in the final analysis, of which 33 patients were randomized to hormonal treatment and 31 to hormonal treatment plus radiation therapy. The presence of fibrosis, number of capillaries, and lymphocyte infiltration was then evaluated by light microscopy.Results: The group receiving radiation therapy had significantly higher LENT/SOMA and function/bother scale scores than the group that only received hormonal treatment, but there was no significant difference in the presence of fibrosis, ectasia, number of capillaries in the lamina propria, or lymphocyte infiltration between the groups.Conclusion: Radiation therapy to 70 Gy to the prostate does not induce long-term microscopic mucosal changes in the rectum 5 years after treatment. This is in contrast to the general assumption that structural changes, including fibrosis, seen after radiation therapy include the mucosa. We speculate that the main late effects of radiation therapy on the structure of the rectum are located in the deeper layers of the rectal wall than the mucosa. [ABSTRACT FROM AUTHOR]

Background Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries. Objectives To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness. Design, setting, and participants Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6–9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker. Results and limitations Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score ≤ 7 tumors. Conclusions This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors. Patient summary The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. [ABSTRACT FROM AUTHOR]

Summary: Background: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5–18·0] vs 9·8 months [7·3–23·7]; hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Interpretation: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding: Algeta and Bayer HealthCare Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Abstract: Context: Prostate cancer (PCa) patients have many options within the realms of surgery or radiation therapy (RT). Technical advancements in RT planning and delivery have yielded different approaches, such as external beam, brachytherapy, and newer approaches such as image-guided tomotherapy or volumetric-modulated arc therapy. The selection of the optimal RT treatment for the individual is still a point of discussion, and the debate centres on two important outcomes—namely, cancer control and reduction of side-effects. Objective: To critically review and summarise the available literature on functional outcomes and rectal sequelae following RT for PCa treatment. Evidence acquisition: A review of the literature published between 1999 and 2010 was performed using Medline and Scopus search. Relevant reports were identified using the terms prostate cancer, radiotherapy, functional outcomes, external beam radiation, brachytherapy, IMRT, quality of life, and tomotherapy and were critically reviewed and summarised. Evidence synthesis: Related to nonuniform definition of their assessed functional end points and uneven standards of reporting, only a minority of series retrieved could be selected for analyses. Moreover, patterns of patient selection for different types of RT, inherent differences in the RT modalities, and the presence or absence of hormonal treatment also limit the ability to synthesise results from different publications or perform meta-analyses across the different treatment types. Nonetheless, several studies agree that recent technical improvements in the field of RT planning and delivery enable the administration of higher doses with equal or less toxicity. Regardless of the type of RT, the most frequently considered functional end points in the published analyses are gastrointestinal (GI) complications and rectal bleeding. Established risk factors for acute or late toxicities after RT include advanced age, larger rectal volume, a history of prior abdominal surgery, the concomitant use of androgen deprivation, preexisting diabetes mellitus, haemorrhoids, and inflammatory bowel disease (IBD). Similarly, mild acute irritative urinary symptoms are reported in several studies, whereas total urinary incontinence and other severe urinary symptoms are rare. Pretreatment genitourinary complaints, prior transurethral resection of the prostate (TURP), and the presence of acute genitourinary toxicity are suggested as contributing to long-term urinary morbidity. Erectile dysfunction (ED) is not an immediate side-effect of RT, and the occurrence of spontaneous erections before treatment is the best predictor for preserving erections sufficient for intercourse. In addition, the use of magnetic resonance imaging (MRI) permits a reduction in the dose delivered to vascular structures critical for erectile function. Conclusions: In the future, further improvement in RT planning and delivery will decrease side-effects and permit administration of higher doses. Related to the anatomy of the prostate, these higher doses may favour rectal sparing while not readily sparing the urethra and bladder neck. As a consequence, there may be a future shift from dose-limiting long-term rectal morbidity towards long-term urinary morbidity. In the absence of prospective randomised trials comparing different types of surgical and RT-based treatments in PCa, the introduction of validated tools for reporting functional and clinical outcomes is crucial for evaluating and identifying each individual''s best treatment choice. [Copyright &y& Elsevier]

Purpose: The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated. Methods and Materials: Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study. Results: Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66% (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score ≥8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18–17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45–4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80–6.62), p < 0.0001. Conclusions: Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis. [ABSTRACT FROM AUTHOR]

Purpose: This study explores the implications for cancer induction of treatment details such as fractionation, planning target volume (PTV) definition, and interpatient variations, which are relevant for the radiation treatment of prostate carcinomas. Methods and Materials: Treatment planning data from 100 patients have been analyzed with a risk model based on the United Nations Scientific Committee on the Effects of Atomic Radiation competition model. The risk model can account for dose heterogeneity and fractionation effects characteristic for modern radiotherapy. Biologically relevant parameters from clinical and experimental data have been used with the model. Results: The results suggested that changes in prescribed dose could lead to a modification of the risks for individual organs surrounding the clinical target volume (CTV) but that the total risk appears to be less affected by changes in the target dose. Larger differences are observed for modifications of the margins between the CTV and the PTV because these have direct impact onto the dose level and dose heterogeneity in the healthy tissues surrounding the CTV. Interpatient anatomic variations also have to be taken into consideration for studies of the risk for cancer induction from radiotherapy. Conclusions: The results have shown the complex interplay between the risk for secondary malignancies, the details of the treatment delivery, and the patient heterogeneity that may influence comparisons between the long-term effects of various treatment techniques. Nevertheless, absolute risk levels seem very small and comparable to mortality risks from surgical interventions, thus supporting the robustness of radiation therapy as a successful treatment modality for prostate carcinomas. [ABSTRACT FROM AUTHOR]

Purpose: Several treatment options are available for patients with prostate cancer. Applicable and valid self-assessment instruments for assessing health-related quality of life (HRQOL) are of paramount importance. The aim of this study was to explore the validity and responsiveness of the intestinal part of the prostate cancer-specific questionnaire QUFW94. Methods and Materials: The content of the intestinal part of QUFW94 was examined by evaluation of experienced clinicians and reviewing the literature. The psychometric properties and responsiveness were assessed by analyzing HRQOL data from the randomized study Scandinavian Prostate Cancer Group 7 (SPCG)/Swedish Association for Urological Oncology 3 (SFUO). Subscales were constructed by means of exploratory factor analyses. Internal consistency was assessed by Cronbach''s alpha. Responsiveness was investigated by comparing baseline scores with the 4-year posttreatment follow-up. Results: The content validity was found acceptable, but some amendments were proposed. The factor analyses revealed two symptom scales. The first scale comprised five items regarding general stool problems, frequency, incontinence, need to plan toilet visits, and daily activity. Cronbach''s alpha at 0.83 indicated acceptable homogeneity. The second scale was less consistent with a Cronbach''s alpha at 0.55. The overall responsiveness was found to be very satisfactory. Conclusion: Two scales were identified in the bowel dimension of the QUFW94; the first one had good internal consistency. The responsiveness was excellent, and some modifications are suggested to strengthen the content validity. [Copyright &y& Elsevier]

Summary: Background: Androgen treatment for prostate cancer can adversely affect functional domains of quality of life. We aimed to assess quality of life in men with locally advanced prostate cancer in an open-label phase III randomised comparison between lifelong endocrine treatment with and without radiotherapy. Methods: We obtained quality-of-life information from 872 (99%) of 875 eligible men with locally advanced prostate cancer (T3; 78%) who were randomly assigned, between 1996 and 2002, to 3 months of total androgen blockade followed by continuous endocrine treatment (439 patients) or the same hormonal treatment with radiotherapy 3 months after randomisation (436 patients). Prospective outcomes included patient-reported symptoms and quality of life assessed with questionnaires from baseline to 4 years after randomisation. Analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787. Findings: 438 of 439 men assigned endocrine treatment and 434 of 436 assigned endocrine plus radiotherapy completed at least one questionnaire. Missing data at baseline and during follow-up was equally distributed between groups. At 4 years, 64 (18%) of 353 patients on combined therapy and 39 (12%) of 337 on endocrine-alone therapy had moderate to severe urinary bother (p=0·005), and 16 (4%) of 355 on combined therapy and five (2%) of 338 on endocrine treatment alone had pain while urinating (p=0·024). 37 (11%) of 350 in the combined group and 23 (7%) of 35 in the endocrine-only group had overall bother from all bowel symptoms (p=0·022). 281 (85%) of 332 in the combined-treatment group and 227 (72%) of 313 in the endocrine-only group had erectile dysfunction (p=0·0002). Quality of life at 4 years was similar, with the exception of decreased social function in patients receiving endocrine treatment plus radiotherapy. Interpretation: Although addition of radiotherapy to endocrine treatment significantly increased some treatment-related symptoms, none were serious. Given the substantial survival benefit of combined treatment, the increase of symptoms seems acceptable and has little extra effect on quality of life after 4 years compared with endocrine treatment alone. Funding: Schering-Plough, Abbott Scandinavia, Nordic Cancer Union, Swedish Cancer Society (070604), Norwegian Cancer Society, Lions Cancer Foundation, and Umeå University. [Copyright &y& Elsevier]

Purpose: Late side effects were prospectively evaluated up to 5 years after dose-escalated external beam radiotherapy (EBRT) and were compared with a previously treated series with conventional conformal technique. Methods and Materials: Bladder and bowel symptoms were prospectively evaluated with the Prostate Cancer Symptom Scale (PCSS) questionnaire up to 5 years posttreatment. In all, 257 patients completed the questionnaire 5 years posttreatment. A total of 168 patients were treated with the conformal technique at doses <71 Gy, and 195 were treated with the dose-escalated stereotactic BeamCath® technique comprising three dose levels: 74 Gy (n = 68), 76 Gy (n = 74), and 78 Gy (n = 53). Results: For all dose groups analyzed together, 5 years after treatment, urinary starting problems decreased and urinary incontinence increased in comparison to baseline values. No increase in other bladder symptoms or frequency was detected. When comparing dose groups after 5 years, both the 74-Gy and 78-Gy groups reported increased urinary starting problems compared with patients given the conventional dose (<71 Gy). No increased incontinence was seen in the 76-Gy or the 78-Gy groups. Bowel symptoms were slightly increased during the follow-up period in comparison to baseline. Dose escalation with stereotactic EBRT (74–78 Gy) did not increase gastrointestinal late side effects after 5 years in comparison to doses <71 Gy. Conclusion: Dose-escalated EBRT with the BeamCath® technique with doses up to 78 Gy is tolerable, and the toxicity profile is similar to that observed with conventional doses <71 Gy. [Copyright &y& Elsevier]

Background: New data suggest that a higher radiation dose will improve outcome in treatment of localized prostate cancer. External beam radiotherapy (EBRT) may on the other hand induce disturbances in the patient''s urinary and intestinal function. Since 1997, 195 patients have been treated with a stereotactic boost of 4–8 Gy added to conventional 70 Gy EBRT. Late side effects were prospectively evaluated 3 years after dose-escalated EBRT.Methods: Urinary and intestinal problems were prospectively evaluated with a validated self-assessment questionnaire, the Prostate Cancer Symptom Scale (PCSS). Two hundred and eighty-seven patients completed the questionnaire at the 1 year follow-up, and 153 at 3 years after treatment. Pre-treatment mean age was 66 years. One hundred and sixty-eight patients were treated with the conformal technique and 195 were treated with the dose-escalated stereotactic BeamCath® technique. Mean total dose in the conformal group (≤70 Gy) was 66 Gy (60.8–70.4 Gy). The dose-escalated group consists of three dose levels, 74 Gy (n=68), 76 Gy (n=74), and 78 Gy (n=53).Results: Analyzing the whole population 3 years after treatment, urgency and starting problems decreased in comparison to pre-treatment. A minor increase in urinary incontinence was reported 3 years after treatment in comparison to pre-treatment. No increases in other urinary symptoms were reported. Intestinal symptoms were slightly increased during the follow-up period in comparison to pre-treatment. Dose escalation with stereotactic EBRT (74–78 Gy) did not increase gastrointestinal or genitourinary late side effects at 1 year or 3 years in comparison to doses ≤70 Gy.Conclusions: The stereotactic BeamCath® EBRT technique facilitates safe dose escalation of patients with prostate cancer. [Copyright &y& Elsevier]